This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Orthostatic hypotension, a sudden, significant drop in blood pressure upon standing, is often associated with diabetes and has many causes. It is a major cause of stroke, exacerbates coexisting coronary or cerebral perfusion, causes falls and injury, impaired quality of life and complicates concurrent medication use. These consequences are exaggerated in the diabetic patient and lead to patient and physician frustration because the therapeutic options have side effects and are frequently ineffective. Very little new data exists relating to the pathophysiology of orthostatic hypotension. We are the first to identify the presence of agonist-like autoantibodies to the autonomic receptors that control major autonomic vascular and cardiac activity in a subgroup of patients with orthostatic hypotension, and to demonstrate their pathophysiological role in such patients. These autoantibodies, often occurring in clusters and observed in patients with diabetes and concurrent cardiac diseases which often have associated orthostatic hypotension, demonstrated significant capacity to activate their respective receptors in biochemical and functional assays. Depending on their relative concentrations and activity, these antibodies produced a spectrum of autonomic dysfunction. In antibody-positive patients, those with rapid resting heart rate had antibodies with predominantly beta-adrenergic activity (positive chronotropic effect), while those with a relatively slow resting heart rate and impaired pulse rate response in the face of orthostatic hypotension had antibodies with predominantly muscarinic activity (negative chronotropic effect). Antibodies to the vasodilatory receptors (beta2-adrenergic and M3 muscarinic) produced an expected potent vasodilatation in the skeletal muscle arteriole assay, suggesting these antibodies may contribute to systemic vasodilatation. A few patients treated with muscarinic blockade (oxybutynin) showed decreased orthostatic symptoms and signs. These data support the hypothesis that antibody activation of autonomic receptors may cause or exacerbate orthostatic hypotension by altering the underlying postural cardiovascular response. Our novel study is the first to examine the association of these autoantibodies in patients with orthostatic hypotension by characterizing the functional effect on their host. These data are also useful in identifying the frequency of their occurrence, their pathophysiological significance and developing therapeutic strategies that pharmacologically target these antibodies.